Cell-surface proteins known as receptors are present on the surface of most if not all of the cells that make up an organism. Cell surface receptors enable chemical communication between the different cells that make up the organism. Typically, cell-cell signaling occurs through the binding of ligands, such as small molecules and proteins, to the various receptors present on the surface of a cell. The binding of ligand to a cell surface receptor can initiate cellular responses (in some examples ligand dissociation initiates a cellular response), which can lead to physiological changes in the cell, for example changes in gene expression patterns and/or chemotactic behavior.
A number of diseases, including cancer, metabolic disorders and viral infections are known to be involved with the expression of cell-surface receptors in their development and/or progression. In the case of viral infection, cell-surface receptors can serve as sites of attachment and entry for viruses, such as human immunodeficiency virus (HIV). In cancer, particularly metastatic progression of cancer, angiogenesis is believed to be mediated by the secretion of growth factors and their binding by cognate receptors on capillary-forming cells. The recognition that cellular surface receptors and their signaling can play a role in human disease has prompted significant research efforts toward the development of pharmaceutical agents that block the signals from cell-surface receptors. For example, agents have been sought that bind the extracellular portion of cell surface receptors and inhibit the binding of the receptor's cognate ligand or agents that bind the intracellular portion of the receptor and prevent signal propagation inside the cell.
The epidermal growth factor receptor (EGFR) has been the target for development of agents that bind the extracellular or intracellular portion of the cell surface receptor. EGFR is frequently overexpressed in a wide range of human tumors. Such overexpression often correlates with poor prognosis and worse clinical outcome. Two classes of anti-EGFR agents have entered clinical practice: monoclonal antibodies and small molecules targeting the receptor tyrosine kinase domain of EGFR. The monoclonal antibodies to EGFR inhibit the binding of EGF to the extracellular domain of EGFR, effectively stopping the signal at the surface of the cell. Small molecules that target the receptor tyrosine kinase domain pass into the interior of the cell where they bind to the EGFR kinase domain and inhibit the catalytic activity of the kinase.
A strategy similar to the EGFR blocking antibodies is being used in the fight against HIV infection. The chemokine receptors CCR5 and CXCR4 were identified as HIV-1 co-receptors in 1996. Since then, a range of agents that bind these receptors and potently block HIV-1 infection have been described, including monoclonal antibodies, peptides and modified chemokines. These anti-HIV agents bind to the chemokine receptors and inhibit the ability of HIV to bind to the chemokine receptors and use them as an entry point into cells.
While the therapeutic approaches described above show great promise for specific applications, the need still exists for new therapeutic strategies that work at the level of cell surface receptors, such as to down-regulate the receptor on the surface of a cell of interest.